The Organizational Hypothesis: Reflections on the 50th anniversary of the publication of Phoenix, Goy, Gerall, and Young (1959)

doi:10.1016/j.yhbeh.2009.03.009

Hormones and Behavior

Volume 55, Issue 5, May 2009, Pages 561-565

https://doi.org/10.1016/j.yhbeh.2009.03.009 Get rights and content

Abstract

The 1959 publication of “Organizing action of prenatally administered testosterone propionate on the tissues mediating mating behavior in the female guinea pig” by Charles H. Phoenix, Robert W. Goy, Arnold A. Gerall, and William C. Young transformed how sex differences in mating behavior were thought to develop. Previous work provided extensive evidence that steroid hormones activated patterns of male and female sexual behavior, but only activated the behavioral patterns typical of a given sex. The 1959 paper explained this phenomenon by arguing that androgens, or their metabolites, acting at specific time(s) during development sexually dimorphically organized the tissues mediating mating behavior, which were activated by appropriate hormonal stimulation in adulthood. Thus, exposure to steroids at specific time(s) permanently altered the structure or function of the organism. The exact hormone, exact timing, exact mechanism, and exact tissues were unspecified in the article. The last two paragraphs of the discussion illustrate the investigators' unresolved views. The first proposes that the ‘organization’ was likely to be functional and not evident in visible structure, whereas the next paragraph argues that behavioral change implies structural change and thus structural changes are the likely consequence of steroid actions. These unresolved issues have produced extensive work in the intervening 50 years. The papers in this issue mark the 50th anniversary of this landmark paper and reflect the scope and relevance of the issues raised in the original paper and demonstrate the progress that has been made in understanding the Organizational Hypothesis and its impact on sexual differentiation.

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Cited by (94)

Cohabitation with receptive females under D2-type agonism in adulthood restores partner preference and brain dimorphism in the SDN-POA following neonatal gonadectomy in male rats
2024, Psychoneuroendocrinology
Perinatal testosterone, or its metabolite estradiol, organize the brain toward a male phenotype. Male rodents with insufficient testosterone during this period fail to display sexual behavior and partner preference for receptive females in adulthood. However, cohabitation with non-reproductive conspecifics under the influence of a D2 agonist facilitates the expression of conditioned partner preference via Pavlovian learning in gonadally intact male rats. In the present experiment, three groups of neonatal PD1 males (N = 12/group) were either gonadectomized (GDX), sham-GDX, or left intact and evaluated for social preferences and sexual behaviors as adults. We then examined whether the effects of GDX could be reversed by conditioning the males via cohabitation with receptive females under the effects of the D2 agonist quinpirole (QNP) or saline, along with the size of some brain regions, such as the sexually dimorphic nucleus of the preoptic area (SDN-POA), suprachiasmatic nucleus (SCN), posterior dorsal medial amygdala (MeApd) and ventromedial hypothalamus (VMH). Results indicated that neonatal GDX resulted in the elimination of male-typical sexual behavior, an increase in same-sex social preference, and a reduction of the area of the SDN-POA. However, GDX-QNP males that underwent exposure to receptive females in adulthood increased their social preference for females and recovered the size in the SDN-POA. Although neonatal GDX impairs sexual behavior and disrupts partner preference and brain dimorphism in adult male rats, Pavlovian conditioning under enhanced D2 agonism ameliorates the effects on social preference and restores brain dimorphism in the SDN-POA without testosterone.
Prenatal androgen exposure and sex-typical play behaviour: A meta-analysis of classic congenital adrenal hyperplasia studies
2024, Neuroscience and Biobehavioral Reviews
Thousands of non-human mammal experiments have demonstrated that early androgen exposure exerts long-lasting effects on neurobehavioural sexual differentiation. In humans, females with classic congenital adrenal hyperplasia (CAH) are exposed to unusually high concentrations of androgens prenatally, whereas prenatal concentrations of androgens in males with CAH are largely normal. The current meta-analysis included 20 independent samples and employed multi-level meta-analytic models. Consistently across all 7 male-typical and female-typical play outcomes, in the expected directions, the present study found significant and large average differences between control males and control females (gs = 0.83–2.78) as well as between females with CAH and control females (gs = 0.95–1.08), but differences between males with CAH and control males were mostly negligible and were non-significant for 6 of the 7 outcomes (gs = 0.04–0.27). These meta-analytic findings suggest that prenatal androgen exposure masculinises and defeminises play behaviour in humans. Broader implications in relation to sex chromosomes, brain development, oestrogens, socio-cognitive influences, other aspects of sex-related behavioural development, and gender nonconformity are discussed.
Effects of perinatal exposures to a TAML catalyst on the mammary gland and hormone-sensitive outcomes in male mice
2024, Reproductive Toxicology
Estrogenic chemicals are common pollutants in wastewater and current effluent treatment processes are not typically effective in removing these compounds. Tetra-amido macrocyclic ligands (TAMLs) are catalysts that mimic endogenous peroxidases that may provide a solution to remove environmental pollutants including low concentrations of estrogenic compounds. Yet relatively little is known about the toxicity of TAMLs, and few studies have evaluated whether they may have endocrine disrupting properties. We administered one of three doses of a TAML, NT7, to mice via drinking water throughout pregnancy and lactation. Two pharmacologically active compounds, ethinyl estradiol (EE2) and flutamide were also included to give comparator data for estrogen receptor agonist and androgen receptor antagonist activities. Male pups were evaluated for several outcomes at weaning, puberty, and early adulthood. We found that EE2 exposures during gestation and the perinatal period induced numerous effects that were observed across the three ages including changes to spleen and testis weight and drastic effects on the morphology of the mammary gland. Flutamide had fewer effects but altered anogenital distance at weaning as well as spleen, liver, and kidney weight. In contrast, relatively few effects of NT7 were observed, but included alterations to spleen weight and modest changes to adult testis weight and morphology of the mammary gland at weaning. Collectively, these results provide some of the first evidence suggesting that NT7 may alter some hormone-sensitive outcomes, but that the effects were distinct from either EE2 or flutamide. Additional studies are needed to characterize the biological activity of this and other TAML catalysts.
Hormonal contraceptive influences on cognition and psychopathology: Past methods, present inferences, and future directions
2022, Frontiers in Neuroendocrinology
Citation Excerpt :
Indeed, the organizational-activational hypothesis states that hormone exposure during sensitive periods of development organizes the brain, and subsequent behavior, in sex-typed ways (that are later activated by circulating hormones). Early androgen exposure, and more recently, the timing of adolescent hormone exposure during puberty, have been shown to be organizational periods for sex-typed brain development in animal models (reviewed in Schulz et al., 2009; Wallen, 2009).2 Natural experimental research in human beings is consistent with this, especially for organizational (but not activational; Puts et al., 2010) effects of androgens on spatial skills (Berenbaum & Beltz, 2011, 2016; Shirazi et al., 2020).
In the last decade, there has been a remarkable surge in research on the neural and behavioral correlates of hormonal contraceptive use, particularly oral contraceptive use. Questions have evolved swiftly and notably, with studies no longer revealing if hormonal contraceptives matter for the brain and behavior, but rather how, when, and for whom they matter most. Paralleling this shift, the goal of this review is to move beyond an average synthesis of hormonal contraceptive influences on human cognition and psychopathology (and their neural substrates) in order to consider the nature and specificity of effects. Accompanied by an evaluation of study methods and informed by findings from animal models, this consideration uncovers promising areas of research in the next ten years, including potential activational and organizational effects of hormonal contraceptive use, individual differences in effects that matter for the wellbeing of unique individuals, and correlates of intrauterine device use.
Killing two birds with one stone: Pregnancy is a sensitive window for endocrine effects on both the mother and the fetus
2022, Environmental Research
Pregnancy is a complex process requiring tremendous physiological changes in the mother in order to fulfill the needs of the growing fetus, and to give birth, expel the placenta and nurse the newborn. These physiological modifications are accompanied with psychological changes, as well as with variations in habits and behaviors. As a result, this period of life is considered as a sensitive window as impaired functional and physiological changes in the mother can have short- and long-term impacts on her health. In addition, dysregulation of the placenta and of mechanisms governing placentation have been linked to chronic diseases later-on in life for the fetus, in a concept known as the Developmental Origin of Health and Diseases (DOHaD). This concept stipulates that any change in the environment during the pre-conception and perinatal (in utero life and neonatal) period to puberty, can be “imprinted” in the organism, thereby impacting the health and risk of chronic diseases later in life. Pregnancy is a succession of events that is regulated, in large part, by hormones and growth factors. Therefore, small changes in hormonal balance can have important effects on both the mother and the developing fetus. An increasing number of studies demonstrate that exposure to endocrine disrupting compounds (EDCs) affect both the mother and the fetus giving rise to growing concerns surrounding these exposures. This review will give an overview of changes that happen during pregnancy with respect to the mother, the placenta, and the fetus, and of the current literature regarding the effects of EDCs during this specific sensitive window of exposure.
Structural, functional, and behavioral significance of sex and gonadal hormones in the basolateral amygdala: A review of preclinical literature
2022, Alcohol
The basolateral amygdala (BLA) is intimately involved in the development of neuropsychiatric disorders such as anxiety and alcohol use disorder (AUD). These disorders have clear sex biases, with women more likely to develop an anxiety disorder and men more likely to develop AUD. Preclinical models have largely confirmed these sex-specific vulnerabilities and emphasize the effects of sex hormones on behaviors influenced by the BLA. This review will discuss sex differences in BLA-related behaviors and highlight potential mechanisms mediated by altered BLA structure and function, including the composition of GABAergic interneuron subpopulations, glutamatergic pyramidal neuron morphology, glutamate/GABA neurotransmission, and neuromodulators. Further, sex hormones differentially organize dimorphic circuits during sensitive developmental periods (organizational effects) and initiate more transient effects throughout adulthood (activational effects). Current literature indicates that estradiol and allopregnanolone, a neuroactive progestogen, generally reduce BLA-related behaviors through a variety of mechanisms, including activation of estrogen receptors or facilitation of GABA_A-mediated inhibition, respectively. This enhanced GABAergic inhibition may protect BLA pyramidal neurons from the excitability associated with anxiety and alcohol withdrawal. Understanding sex differences and the effects of sex hormones on BLA structure and function may help explain sex-specific vulnerabilities in BLA-related behaviors and ultimately improve treatments for anxiety and AUD.

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CommentaryThe Organizational Hypothesis: Reflections on the 50th anniversary of the publication of Phoenix, Goy, Gerall, and Young (1959)

Abstract

Horm. Behav.

Neurosci. Biobehav. Rev.

Psychoneuroendocrinology

Hormonal factors controlling the differentiation, development, and display of copulatory behavior in the ramstergig and related species

Mating behavior in male rats castrated at various ages and injected with androgen

J. Exp. Zool.

Effects of androgen on the glans penis and mating behavior of castrated rats

J. Exp. Zool.

Effects of perinatal androgen treatment on responses of male rats to gonadal hormones in adulthood

J. Comp. Physiol. Psychol.

Miscellaneous experiments on the estrogen-progesterone in induction of heat in the spayed guinea-pig

Endocrinology

Quantitative studies of experimentally induced sexual receptivity in the spayed guinea-pig

Endocrinology

Feminine behavior in neonatally castrated and estrogen-treated male rats

Science

Progesterone concentrations in the arterial plasma of guinea-pigs during the oestrous cycle

J. Endocr.

Recollections of the origins and reactions to the organizational concept

Horm. Behav.

Commentary
The Organizational Hypothesis: Reflections on the 50th anniversary of the publication of Phoenix, Goy, Gerall, and Young (1959)